Editor’s Note
The European Society for Medical Oncology (ESMO) 2025 Annual Congress, held in Berlin, Germany from October 17–21, gathered leading global experts to share groundbreaking advances in cancer diagnosis and treatment.
A retrospective study led by Prof. Guiying Xu from Jilin Cancer Hospital, titled “Consistency of PIK3CA Mutations Between Primary and Recurrent/Metastatic Lesions in HR+/HER2– Breast Cancer”, was selected for poster presentation (Abstract #529P). This study provides valuable real-world data for PIK3CA testing in Chinese clinical practice.
Focusing on the PIK3CA mutation status and clinical significance in both primary and recurrent/metastatic lesions of HR+/HER2– breast cancer patients, the study offers key insights to guide treatment decision-making during disease progression.
Background and Objectives
Hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer is one of the most common subtypes of breast cancer. Despite progress with endocrine and targeted therapies, tumor progression and treatment resistance remain major challenges.
Numerous studies have shown that PIK3CA mutations occur frequently in HR+/HER2– breast cancer and are closely associated with endocrine resistance and tumor progression. Consequently, PIK3CA has become a key molecular target in this subtype.
According to current guidelines and expert consensus, patients with advanced HR+/HER2– breast cancer should undergo PIK3CA mutation testing prior to first-line therapy to guide prognosis assessment and individualized treatment planning.
However, in real-world clinical settings, several practical challenges remain:
- Difficulty obtaining metastatic tissue samples, especially from deep or inaccessible sites (e.g., lung, liver, bone, brain), where biopsy carries risks such as bleeding or pneumothorax.
- Some patients have poor general condition or small metastatic lesions, making adequate sampling difficult.
- Limited awareness of PIK3CA testing among patients and clinicians.
- Inconsistent testing methodologies and lack of standardized processes across institutions.
These barriers highlight the need for standardized and optimized testing workflows to better integrate PIK3CA mutation detection into routine clinical practice.
Despite growing interest, there has been a lack of evidence evaluating the concordance of PIK3CA mutations between primary and metastatic tumors in HR+/HER2– breast cancer. Few studies have systematically compared mutation patterns in paired primary and metastatic samples, leaving uncertainty in guiding targeted therapy decisions.
This study analyzed paired primary and metastatic tumor samples from 44 Chinese HR+/HER2– metastatic breast cancer patients treated at Jilin Cancer Hospital. Using real-time fluorescent PCR, researchers examined the distribution, consistency, and clinical relevance of PIK3CA mutations to support precision oncology and individualized treatment decision-making.
Methods
Sample Collection, Testing, and Statistical Analysis
This retrospective cohort study included patients diagnosed between November 2012 and August 2024 at Jilin Cancer Hospital.
A total of 97 HR+/HER2– metastatic breast cancer patients were screened, and 44 with paired primary and metastatic tumor samples were included for analysis. Patients with other malignancies or failed PIK3CA testing were excluded.
PIK3CA mutation testing was performed using the AmoyDx® PIK3CA Mutation Detection Kit via real-time quantitative PCR.
Key analyses included:
- Comparison of mutation status and hotspot distribution between primary and metastatic lesions.
- Concordance analysis using Cohen’s kappa coefficient.
- Descriptive statistics for patient characteristics and mutation frequencies.
All analyses were performed using R software (version 4.4.0).
Patient Characteristics
A total of 44 HR+/HER2– breast cancer patients with paired primary and metastatic samples were included.
- Mean age: 47.9 ± 9.9 years.
- Age distribution: 59.1% >50 years; 40.9% ≤50 years.
- Median BMI: 23.9 ± 2.8.
- Menopausal status: 52.3% postmenopausal.
- Disease stage at diagnosis: Stage I (40.9%), Stage II (47.7%), Stage III (6.8%), Stage IV (4.5%).
- T-stage: T1 (56.8%), T2 (38.6%).
- N-stage: N0 (65.9%), N1 (29.5%), N2 (4.5%).
- Metastasis: 95.5% M0; 4.5% M1.
- Pathology: 95.5% invasive carcinoma.
Overall, the study population mainly comprised middle-aged and postmenopausal women with early-stage invasive breast cancer, providing a representative basis for molecular and clinical analysis.
Results
Distribution and Hotspot Mutations of PIK3CA
Among the 44 HR+/HER2– patients analyzed:
- PIK3CA mutations were detected in 18 primary tumors (40.9%) and 15 metastatic tumors (34.1%).
- The most frequent mutation was H1047R, found in 18.2% of primary lesions (8 cases) and 13.6% of metastases (6 cases).
- E542K mutations occurred in 13.6% (6 cases) of primaries and 11.4% (5 cases) of metastases.
- E545K mutations were found in 6.8% (3 cases) of both primary and metastatic samples.
- Among different metastatic sites, PIK3CA mutation rates ranged from 31.1% to 38.1% in bone and lung lesions, while no mutations were detected in the single case of liver metastasis.
These findings indicate that PIK3CA mutations are common in this population, with H1047R, E542K, and E545K as the predominant hotspots, underscoring the clinical value of molecular testing for this gene.
Concordance Between Primary and Metastatic Lesions
Analysis of paired samples from 44 patients revealed a high concordance rate (93.2%) for PIK3CA mutation status between primary and metastatic lesions, with a Cohen’s kappa coefficient of 0.855, indicating strong agreement.
Among the 15 patients with PIK3CA-mutant metastases, all had matching mutations in their corresponding primary tumors, with identical hotspot sites.
Of the 29 patients whose metastases were PIK3CA wild-type, only three had mutations detected in the primary tumor.
These results demonstrate that the PIK3CA mutation profile remains largely stable throughout disease progression, providing a reliable molecular marker for guiding therapy.
Conclusions
Clinical Implications and Future Directions
This study systematically evaluated the distribution and concordance of PIK3CA mutations between primary and metastatic tumors in Chinese HR+/HER2– breast cancer patients, providing important evidence for precision treatment strategies.
The results showed an overall mutation concordance of 93.2% (Cohen’s kappa = 0.855), confirming that PIK3CA mutation status remains consistent during disease progression.
- Mutation frequency: 40.9% in primary tumors, 34.1% in metastases.
- Hotspot sites: H1047R, E542K, and E545K.
- All PIK3CA-mutant metastases shared identical mutations with their corresponding primary tumors.
These findings have direct clinical relevance: for patients being considered for PIK3CA inhibitor therapy, testing either the primary or metastatic site is sufficient—reducing the need for repeated biopsies and minimizing procedural risks.
After expanding the dataset to 63 eligible patients (up to May 2025), similar results were observed:
- Lymph node metastasis concordance: 93.1% (Cohen’s kappa = 0.854).
- Chest wall metastasis concordance: 90.0% (Cohen’s kappa = 0.754).
- Among 17 patients with lymph node samples, concordance rates were 88.2% between primary and lymph node lesions, 100% between lymph nodes and recurrent/metastatic lesions, and 88.2% among all three sites.
Survival analysis showed median recurrence-free survival of 44.5 months in patients with PIK3CA-mutant primaries and 35.2 months in wild-type cases (Log-rank P > 0.05).
Future studies should expand to multicenter cohorts and incorporate treatment and outcome data to explore the prognostic and therapeutic implications of specific PIK3CA mutation subtypes, as well as the mechanisms driving mutation changes and therapy resistance.
Investigator’s Commentary
“This retrospective analysis of Chinese HR+/HER2– breast cancer patients revealed a remarkably high concordance (93.2%, Cohen’s kappa = 0.855) of PIK3CA mutation status between primary and metastatic tumors,” said Prof. Guiying Xu of Jilin Cancer Hospital.
“Hotspot mutations were concentrated at H1047R, E542K, and E545K, and mutation types were completely consistent between paired samples. The study population had a mean age of 47.9 years, mainly postmenopausal and early-stage at diagnosis.”
“These findings suggest that, in Chinese HR+/HER2– breast cancer patients, PIK3CA mutation results from primary tumors are highly representative of metastatic lesions, providing strong evidence to guide targeted treatment decisions and further investigations into the biological role of PIK3CA in disease progression.”
Prof. Guiying Xu
Director, Department of Breast Oncology II Jilin Cancer Hospital
